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Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel-group study of lamotrigine.

ABSTRACT: AIM:A new strength of lamotrigine extended-release formulation unexpectedly failed to show bioequivalence with the existing strengths at the same dose in a parallel-group study. We report the post-hoc analyses conducted to identify the cause and propose an approach for future evaluations in similar situations. METHODS:A seemingly bimodal distribution of the half-life among the study participants prompted the use of terminal-phase-rate-constant-adjusted area under the concentration curve as the endpoint for bioequivalence assessment. Population pharmacokinetic modelling was also performed to assess the bimodal distribution of apparent clearance and the potential treatment effects on bioavailability. RESULTS:The cause for failing to achieve bioequivalence appeared to be a biased representation of a bimodal clearance distribution between the groups. The pharmacokinetic modelling with a mixture routine identified two subpopulations: 88% had a mean clearance of 1.99 l h-1 ; 12% had a mean clearance of 0.64 l h-1 . The low-clearance population was unequally represented by 13% and 4% of subjects in the reference and test groups, respectively, and treatment appeared to have no significant effect on oral bioavailability. The bioequivalence comparison using the adjusted area concluded with a 90% confidence interval of 0.91-1.06, suggesting that treatment had no significant effect on bioavailability and the formulations would meet regulatory criteria for bioequivalence. CONCLUSIONS:The adjustment of the area under the concentration curve adjusted by terminal-phase rate constant should be considered for situational application in bioequivalence assessment when there are multiple clearance subpopulations in a parallel-group study.

SUBMITTER: Yang J

PROVIDER: S-EPMC6379210 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel-group study of lamotrigine.

Yang Jiansong J Ma Peiming P Bullman Jonathan J Nicholls Andrew A Chen Chao C

British journal of clinical pharmacology 20190117 3

<h4>Aim</h4>A new strength of lamotrigine extended-release formulation unexpectedly failed to show bioequivalence with the existing strengths at the same dose in a parallel-group study. We report the post-hoc analyses conducted to identify the cause and propose an approach for future evaluations in similar situations.<h4>Methods</h4>A seemingly bimodal distribution of the half-life among the study participants prompted the use of terminal-phase-rate-constant-adjusted area under the concentration ...[more]

PMID: 30511473

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Project description:ImportanceSwitching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs.ObjectiveTo evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products.Design, setting, and participantsThe Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses.InterventionsParticipants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected.Main outcomes and measuresThe primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%).ResultsOf the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76).Conclusions and relevanceThis study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs.Trial registrationclinicaltrials.gov Identifier: NCT01733394.

Project description:AIM:To develop a vancomycin population pharmacokinetic model and assess the probability of attaining a pharmacodynamic target associated with clinical and microbiological success, a ratio of the 24-hour area under the concentration-time curve to the minimum inhibitory concentration (MIC) ? 400, in a 5-year clinical cohort of preterm and term neonatal patients with late-onset staphylococcal sepsis. METHODS:Therapeutic drug monitoring data were obtained from septic neonates with ?1 vancomycin concentration(s) from January 2006 to September 2011. Only neonates with a postnatal age of >72 hours and a positive microbiological culture were included. Population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM 7.2). Eleven demographic characteristics were evaluated as covariates. Probabilities of achieving the pharmacodynamic target were evaluated. RESULTS:A 1-compartment model with first-order elimination was constructed from 528 vancomycin concentrations collected from 152 preterm and term neonates. Body weight, creatinine clearance (CL), and postmenstrual age were identified as significant covariates. Estimated vancomycin CL and volume of distribution for typical neonates were 0.068 ± 0.03 L·h·kg and 0.62 ± 0.13 L/kg, respectively. Coagulase-negative staphylococci (85.5%) and Staphylococcus aureus (14.5%) were the common pathogenic organisms. The distribution of vancomycin MIC breakpoints was composed of approximately 70% MIC breakpoint of ?2 mcg/mL. Approximately 54% of neonates, with a median serum creatinine concentration of 0.44 mg/dL, achieved the target ratio of 24-hour area under the concentration-time curve to the MIC ? 400 with a median daily dose of 30 (interquartile range, 21-42) mg/kg. CONCLUSIONS:Body weight, creatinine CL, and postmenstrual age significantly influenced vancomycin CL. The current vancomycin doses are acceptable at MICs ?1 mcg/mL because they are likely to achieve the pharmacodynamic target in the majority of neonatal patients, although higher doses may be considered for more resistant staphylococcal infections.

Dataset Information

Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel-group study of lamotrigine.

Publications

Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel-group study of lamotrigine.

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